Antiviral therapy is effective in preventing AIDS in HIV-infected people. However, an increasing number of HIV infected individuals suffer or even die of diseases other than AIDS including cardiovascular diseases. The biology behind these clinical observations is not well understood, although both anti-retroviral therapy (ART) dependent and independent mechanisms appear to be involved. Here we plan to study a key mechanism by which HIV can cause endothelial activation and dysfunction, which are believed to precede atherosclerotic processes. Nef is known to play a pivotal role in HIV pathogenesis and to mediate its own transfer from T cells to bystander cells. Therefore, we postulate that HIV-Nef can efficiently be transferred from T cells to other blood cells including vascular endothelial cells, which are in steady contact with flowing blood and lymph fluid. Indeed, we can show that transfer of Nef leads to endothelial cell activation and cell death, which can be effectively abrogated by NADPH oxidase inhibitors and antioxidants. Based on our published data that HIV dependent endothelial activation can be explained by transfer of Nef from blood cells to coronary arterial endothelial cells, we further hypothesize that transfer of Nef to vascular cells may lead to cardiovascular dysfunction and pathology of the cardiovascular system. We plan to address in preclinical in vitro and in vivo models the mechanism of Nef transfer to and activity in endothelial cells. We expect that identifying such targets will enable clinical interventions studis with appropriate inhibitors. Thus, determining the cellular mechanism of Nef-induced vascular pathology in vascular endothelial cells can help to identify HIV-Nef as a novel target for preventing and treating HIV- associated diseases.